Impact of Host NF-kB Signaling in Radiation Therapy

项目摘要/摘要 不同细胞表面诱导的胞质到核(C→N)核因子-κB信号通路的研究 受体极大地扩展了关于该转录因子家族在 调节免疫/炎症反应和肿瘤发生。相比之下，DNA的生理作用 损伤诱导的核-胞浆(N-→-C)核转录因子-κB信号仍然知之甚少。建议数 这项研究将通过阐明N-→C-NF-κB信号在维持生命周期中的惊人和关键作用来填补这一知识空白 体内放射治疗中抗肿瘤CD8 T细胞反应的研究目前的提案利用了一种基因 体内选择性禁用N-→-C、NF-κB信号的改良小鼠模型。我们的初步数据显示， 放射治疗可以通过依赖CD8 T细胞的方式诱导同基因肿瘤的持续消退。 我们还发现，与肿瘤控制有关的一种特殊类型的记忆CD8 T细胞在这只小鼠中得到了扩增 模特。最后，我们用核因子-kB DNA结合抑制剂产生了一个令人鼓舞的数据来诱导持续的 放射治疗后肿瘤消退。基于这些观察，我们假设抑制 宿主中的N→C、NF-κB信号通过产生肿瘤抗原特异性记忆改善放射治疗 CD8T细胞。我们将通过定义持续肿瘤控制介导的细胞机制来检验这一假说 通过在放射治疗中抑制宿主N-→C-NF-κB信号(目标1)，阐明其分子机制 放射治疗中抑制宿主N-→-C、NF-κB信号介导的持续肿瘤控制(目标2)和靶点 宿主N、→、C、NF-κB使用化学抑制物信号转导以改善放射治疗(目标3)。建议的研究是 重要的是因为N→C NF-κB信号在调节宿主肿瘤反应中的生理作用是 完全没有定义，这项研究将填补这一知识空白。这是创新的，因为新的鼠标型号和 目前正在进行第二阶段临床试验的一种新型化学抑制剂将被使用。最后，一个很大的影响是 因为上述抑制剂对N-→C-NF-κB信号的化学靶向可能会及时加快 转化为临床试验。

PROJECT SUMMARY / ABSTRACT Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface receptors has significantly expanded the knowledge regarding the role of this transcription factor family in regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells. We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely translation to clinical trials.